A TIMELESS link to dedifferentiation in thyroid cancer

TIMELESS is considered a molecular hinge linking circadian rhythms and the cell cycle. We recently identified TIMELESS as one of the upregulated core circadian clock genes during thyroid cancer dedifferentiation, but its expression and significance in thyroid cancer remain unclear. To address this, we assessed TIMELESS expression in thyroid neoplasms using bioinformatics analysis, immunoblotting, and immunohistochemistry. TIMELESS expression progressively increased from normal thyroid tissue to differentiated thyroid cancer and then to anaplastic thyroid cancer. Silencing TIMELESS expression in thyroid cancer cells reduced clonogenicity and spheroid formation, induced G2/M cell cycle arrest, and impeded xenograft growth in NOD SCID mice. In The Cancer Genome Atlas, TIMELESS expression was negatively correlated with recombination proficiency scores. Knocking down TIMELESS increased sensitivity to doxorubicin in thyroid cancer cells and upregulated the mRNA expression of NKX2-1 and SLC5A5. In conclusion, the overexpression of TIMELESS is associated with thyroid cancer dedifferentiation and may serve as a potential target for combination therapies.